Turgeon J, Funck-Brentano C, Gray H T, Pavlou H N, Prakash C, Blair I A, Roden D M
Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232-6602.
Clin Pharmacol Ther. 1991 May;49(5):488-96. doi: 10.1038/clpt.1991.59.
Encainide metabolism is mediated by the polymorphically distributed cytochrome P450IID6, which displays stereoselectivity for some substrates. In this study we found that urinary recovery during steady-state encainide in three poor metabolizers was high (49% to 80%), consisted mainly of unchanged encainide, was nonstereoselective (+/- ratio, 0.985 to 1.049), and was unchanged by quinidine, a potent inhibitor of P450IID6. In contrast, in seven extensive metabolizers the +/- urinary ratios were 1.20 +/- 0.06 for encainide and 0.81 +/- 0.06 (both p less than 0.01) for the cytochrome P450IID6 products O-desmethylencainide plus 3-methoxy-O-desmethylencainide; with quinidine the total percentage recovery rose from 4% +/- 4% to 37% +/- 9% because of increased recovery of unchanged encainide and became non-stereoselective (+/- ratio, 0.84 +/- 0.08 [encainide alone] versus 0.97 +/- 0.05 [encainide plus quinidine]). In vitro, encainide enantiomers depressed the maximum rate of metabolism with similar frequency and concentration dependence. We conclude that (-)-encainide undergoes preferential metabolism by cytochrome P450IID6; however, this genetically determined stereoselective disposition is unlikely to play a major role in mediating the clinical actions of encainide.
恩卡尼的代谢由多态分布的细胞色素P450IID6介导，该酶对某些底物表现出立体选择性。在本研究中，我们发现三名慢代谢者在恩卡尼稳态期间的尿回收率很高（49%至80%），主要由未变化的恩卡尼组成，无立体选择性（±比值，0.985至1.049），并且不受P450IID6的强效抑制剂奎尼丁的影响。相比之下，在七名快代谢者中，恩卡尼的±尿比值为1.20±0.06，细胞色素P450IID6产物O-去甲基恩卡尼加3-甲氧基-O-去甲基恩卡尼的±尿比值为0.81±0.06（两者p均小于0.01）；使用奎尼丁后，由于未变化的恩卡尼回收率增加，总回收率从4%±4%升至37%±9%，并变得无立体选择性（±比值，单独恩卡尼为0.84±0.08，恩卡尼加奎尼丁为0.97±0.05）。在体外，恩卡尼对映体以相似的频率和浓度依赖性抑制最大代谢率。我们得出结论，（-）-恩卡尼经细胞色素P450IID6优先代谢；然而，这种由基因决定的立体选择性处置不太可能在介导恩卡尼的临床作用中起主要作用。
